Beta2-adrenoceptor signaling is required for the development of an asthma phenotype in a murine model

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 7; pp. 2435 - 2440
• Main Authors: Nguyen, Long P, Lin, Rui, Parra, Sergio, Omoluabi, Ozozoma, Hanania, Nicola A, Tuvim, Michael J, Knoll, Brian J, Dickey, Burton F, Bond, Richard A
• Format: Journal Article
• Language: English
• Published: United States 17.02.2009
• Subjects: Alprenolol - pharmacology; Animals; Asthma - genetics; Asthma - pathology; Bronchoconstrictor Agents - pharmacology; Disease Models, Animal; Epithelial Cells - metabolism; Humans; Lung - pathology; Methacholine Chloride - pharmacology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Phenotype; Receptors, Adrenergic, beta-2 - metabolism; Signal Transduction
• ISSN: 1091-6490
• DOI: 10.1073/pnas.0810902106

Chronic regular use of beta(2)-adrenoceptor (beta(2)-AR) agonists in asthma is associated with a loss of disease control and increased risk of death. Conversely, we have found that administration of beta(2)-AR inverse agonists results in attenuation of the asthma phenotype in an allergen-driven murine model. Besides antagonizing agonist-induced signaling and reducing signaling by empty receptors, beta-AR inverse agonists can also activate signaling by novel pathways. To determine the mechanism of the beta-AR inverse agonists, we compared the asthma phenotype in beta(2)-AR-null and wild-type mice. Antigen challenge of beta(2)-AR-null mice produced results similar to what was observed with chronic beta(2)-AR inverse agonist treatment, namely, reductions in mucous metaplasia, airway hyperresponsiveness (AHR), and inflammatory cells in the lungs. These results indicate that the effects of beta(2)-AR inverse agonists are caused by inhibition of beta(2)-AR signaling rather than by the induction of novel signaling pathways. Chronic administration of alprenolol, a beta-blocker without inverse agonist properties, did not attenuate the asthma phenotype, suggesting that it is signaling by empty receptors, rather than agonist-induced beta(2)-AR signaling, that supports the asthma phenotype. In conclusion, our results demonstrate that, in a murine model of asthma, beta(2)-AR signaling is required for the full development of three cardinal features of asthma: mucous metaplasia, AHR, and the presence of inflammatory cells in the lungs.